Title

Authors

Date of Completion

January 2002

Keywords

Biology, Neuroscience|Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Drug delivery into the central nervous system is often restricted by the blood-brain barrier (BBB), composed of the endothelial cells lining the microvasculature in the brain. The presence of tight intercellular junctions between these cells as well as low pinocytotic activity, lack of fenestrations and metabolic activity accounts for selective molecular transfer into the brain. It is now understood that lipophilicity alone is not the sole predictor of transfer across this barrier. The process by which a compound traverses this barrier is extremely complicated and bulk physicochemical properties can only provide limited information. Cell culture models employing brain microvessel endothelial cells (BMECs) can increase our understanding of the features by which molecules gain entry to the brain by mimicking the BBB. ^ Cannabinergic agents, including natural products derived from marijuana, endogenous ligands and synthetic analogs, have demonstrated activity as antiemetics and appetite stimulants. Cannabinergic antagonists are also being developed as appetite suppressants and may also have promise as experimental therapies for multiple sclerosis and cocaine abuse. These therapeutic avenues rely on the activity of cannabinergics in the brain. It is therefore important to ascertain if these ligands are capable of traversing the BBB. Using a BMEC model system, the disposition of cannabinergic agents was studied. ^ Specifically, we have established primary and immortalized BMEC culture models of the BBB using bovine brains. These cultures were found to possess biochemical and morphologic characteristics common to the BBB in vivo . Using these cell systems, the ability of a representative series of cannabinergic ligands to cross the model BBB was assessed. Cannabinergic ligand transport was not found to be enantioselective and was predominantly passive. However, facilitated transport into the brain was found to exist for an endocannabinoid. Additionally, we have determined the presence of an enzyme responsible for the hydrolysis of endocannabinoids as well as a putative novel cannabinoid or cannabinoid-like receptor in our BBB model. Lastly, preliminary evidence has been obtained demonstrating that certain cannabinergic ligands are actively transported out of the brain. Thus, this work has characterized the disposition of a series of cannabinergic ligands in a model of the BBB. ^

Recommended Citation

Ayotte, Lionel Alfred, "The disposition of cannabinergic ligands in an in vitro model of the blood-brain barrier" (2002). Doctoral Dissertations. AAI3062068.
https://opencommons.uconn.edu/dissertations/AAI3062068